The unifying theme of this program project is the use of genetic approaches, e.g., transgenic methods, gene knockout, gene mapping, and mitochondrial transfer, to develop new mouse models of several very important human diseases. A major strength of this program project is that it brings together the diversity of expertise required to develop these valuable model systems. The investigators of this project have a well established track record of working together effectively. We have proposed to target 6 human diseases that have major health care impact, as follows: Project 1 will, using transgenes of the regulatory sequences of phosphoenolpyruvate carboxykinase and medium-chain acyl-CoA dehydrogenase in the nonobese diabetic (NOD) mouse, develop new transgenic models to study the molecular mechanisms involved in hyperglycemia and ketogenesis of insulin-dependent diabetes mellitus. Project 2 has as its primary aim the development of methods by which foreign mitochondria can be introduced into the mouse germ-line, initially by microinjection of foreign mitochondria into fertilized mouse eggs. This could have a major influence on development of mouse models of mitochondrial genetic diseases. Project 3 will identify and characterize the genes that determine host resistance vs. susceptibility to Mycoplasma pulmonis infection in mice. The identification of these genes and the effector mechanisms they control could have a major impact on our understanding of pneumonia and antibacterial defenses in the lungs. Project 4 concerns the development of transgenic mouse models of prostate cancer through the use of prostate- specific promoters to overexpress growth factors, that have been implicated in prostatic neoplasia. Project 5 will develop a model that is susceptible to infection with human measles virus by developing a transgenic mouse expressing human CD46 (measles receptor) gene under control of its natural promoter. Project 6 will develop a mouse model that has no beta-amyloid precursor protein background, so that transgenic experiments with human Alzheimer's disease beta-amyloid precursor alleles can be pursued successfully. All of these projects will be supported by a Transgenic Animal/ES Cell Core and a Pathology Core.